Tier 3 — preclinical

Pharmacological activation of SIRT6 suppresses progression of head and neck and esophageal squamous cell carcinoma by modulation of cellular metabolism and protein translation

Talal Ben Lulu, Dinesh Babu Manikandan, Yaniv Pevzner, Menachem Sklarz, Sarah Adi Eisdorfer, Samaa Awad, Sooraj Mathukkada, Divyasree Marripati, Monica Wainer, Liana Shimshilashvili-Kleiner, Ehud Ohana, Idan Cohen, Jian Zhang, Shatha S Alassam, Barak Rotblat, Hai Wang, Dexin Kong, Ofir Cohen, Debra Toiber, Moshe Elkabets
Cell Death & Disease 2025 16(1):727

Bibliography

PubMed
PMID 41102169
DOI
10.1038/s41419-025-07959-5
Funding
Israel Science Foundation grant 302/21.
Competing interests
Authors declared no competing interests.

Study snapshot

DesignCancer-cell and xenograft pharmacology study with multi-omic/metabolic pathway analysis.
ModelHead and neck and esophageal squamous-cell carcinoma cell lines and cell-derived xenografts.
SampleMultiple cell lines and xenograft experiments; exact group sizes vary.
InterventionMDL-800 alone and combined with PI3K-alpha inhibitor alpelisib/BYL719.
DurationModel-specific.
EndpointsCell proliferation and migration; Xenograft growth; H3K9 acetylation; mTOR signaling; Protein translation; Glucose metabolism; Combination response

What the study showed, in plain terms

MDL-800 SIRT6 activation slowed head-and-neck and esophageal squamous-cancer growth in cells and xenografts by suppressing metabolism and protein translation. Combining it with PI3K-alpha inhibition produced a stronger anti-tumor response.

Key findings

MDL-800 reduced proliferation, migration and xenograft growth; mTOR suppression triggered a compensatory IGF-1R/INSR loop that was overcome by alpelisib combination treatment.

What this study can and cannot tell us

Preclinical oncology evidence cannot be transferred to cancer prevention or supplement use. The effect is specific to tumors in which SIRT6 is downregulated or tumor-suppressive.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability